About 1-3% of all women undergo precocious menopause, either never going through menarche or stopping menstruation by the mid-30's, rather than reaching the standard reproductive lifespan of about 50. A fraction of such instances of early-onset "premature ovarian failure (POF)" is genetic. A single locus on chromosome 3 is implicated in several families and in several isolated individuals with translocations or deletions that interrupt the DNA in that region. In collaboration with the group of Dr. G. Pilia, we have isolated the gene in which mutations cause POF, and are analyzing its function; it appears to function as a rheostat, determining the number of follicles by the level of its function. A much larger group of translocations have been reported on the X chromosome, centering on a critical region of the long arm. There we have shown that based on the physical map we had constructed, there are at least 35 distinct X chromosome loci at which translocations can produce POF. We have begun further molecular analyses of the sequences spanning translocation breakpoints. Two have been analyzed in detail at the sequence level, and one of those falls outside of any gene, in a region of repetitive sequence elements. This increases the possibility that some X translocations act by interrupting chromosome dynamics during meiosis, whereas others may cause POF by the interruption of specific genes involved in follicle formation or stability. In an associated project, we are using gene expression profiling on microarrays of 15K mouse cDNAs (the NIA array in the annual report of the group of Dr. M. Ko (LG)) to assess the gene cohorts involved in ovarian development. The studies will be combined with analyses of genes whose function is sharply affected in hereditary POF, using a mouse model that is under construction with the targeted disruption of the chromosome 3 candidate gene.